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Biological effects of ionizing radiations..what every physician must know

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Biological effects of ionizing radiations..what every physician must know

  1. 1. Biological effects of ionizing radiations what every physician must know Dr/Ahmed bahnassy Consultant radiologist PSMMC
  2. 2. Aims of lecture • To become familiar with the mechanisms of different types of biological effects following exposure to ionizing radiation. • To be aware of the models used to derive risk coefficients for estimating the detriment. Radiation injury from an industrial source
  3. 3. Ionizing Radiation The weapon Ionizing Radiation is the removal of an electron from an atom leaving an unstable molecule which may then break apart to form free radicals. http://www.paradigmlink.com/ionrad.shtml
  4. 4. Linear Energy Transfer (LET) The average energy deposited per unit length of track. Measured in kiloelectron volts per micron (10-6 m)
  5. 5. Low LET / High LET e-  Low LET Low mass, increased travel distance (gamma rays, xrays). Sparsely ionizing with random interactions. Causes damage primarily through indirect action or may cause single strand breaks (which are repairable). http://staff.jccc.net/PDECELL/biochemistry/dna.gif
  6. 6. Low LET / High LET High LET α++ – Large mass, decreased travel distance (alpha particles, protons, low energy neutrons). – Causes dense ionization along its path with a high probability of interacting directly with DNA. http://staff.jccc.net/PDECELL/biochemistry/dna.gif
  7. 7. Ionizing Radiation The following are the most common types of ionizing radiation:  Alpha particles  The alpha particle has a large mass and consists of two protons, two neutrons and no electrons (+2)  The alpha particle deposits a large amount of energy in a short distance of travel (about 1-2 inches)  Most alpha particles are stopped by a few centimeters of air, a sheet of paper, or the dead layer (outer layer) of skin.  Beta particles  The beta particle has a small mass and is negatively charged (-1)   Beta radiation causes ionization by displacing electrons from their orbits.  Because of its negative charge, the beta particle has a limited penetrating ability.   Range in air is about 10 feet. http://www.paradigmlink.com/ionrad.shtml
  8. 8. Ionizing Radiation  Gamma rays/x rays  Gamma/ x ray radiation is an electromagnetic wave or photon  and has no electrical charge Gamma/ x ray radiation can ionize as a result of direct interactions with orbital electrons and  is transmitted directly to its target.  Because Gamma/ x ray radiation have no charge and no mass, it has a very high penetrating power.    Neutron particles  Neutron radiation consists of neutrons that are ejected from   the nucleus and have no electrical charge Due to their neutral charge, neutrons interact with matter either directly or indirectly Because of the lack of a charge, neutrons have a relatively high penetrating ability and are difficult to stop.  http://www.paradigmlink.com/ionrad.shtml
  9. 9. Ionizing Radiation The injury mechanism The reactions caused by ionizing radiation occur rapidly, they are nonselective and random. The majority of damage caused by radiation is due to chemical reactions with water within the cell.
  10. 10. H 2O water HOH + Positively charged water molecule e- electron Radiation reacts with water to produce an electron and a positively charged water molecule.
  11. 11. H 2O water HOH + Positively charged water molecule e- + electron H 2O water HOH - negatively charged water molecule The electron reacts with another water molecule to produce a negatively charged water molecule
  12. 12. H+ H 2O water HOH + Hydrogen ion Positively charged water molecule e- electron + H 2O water HOH - negatively charged water molecule OH * Hydroxyl radical The positively charged water molecule dissociates into a hydrogen ion and a hydroxyl radical.
  13. 13. H+ H 2O Hydrogen ion water HOH + Positively charged water molecule e- electron + H 2O water HOH - negatively charged water molecule H* hydrogen radical OH Hydroxyl ion OH * Hydroxyl radical The negatively charged water molecule dissociates into a hydrogen radical and a hydroxyl ion.
  14. 14. Reactions The previous reactions produce free electrons (e-), the ions H- and OH-, the free radicals H* and OH*. The fate of these products are…….
  15. 15. H 2O H+ HOH + e - + H 2O OH * HOH - H* OH The positively charged water molecule and the electron recombine to form water. HOH + + e- H 2O
  16. 16. H 2O H+ HOH + e - + H 2O OH * HOH - H* OH The ions combine to form water. H+ + OH - H 2O
  17. 17. H 2O H+ HOH + e - + H 2O OH * HOH - H* OH The radicals combine to form water. H* + OH * H 2O
  18. 18. H 2O H+ HOH + e - + H 2O OH * OH* HOH H* OH The hydroxyl radical reacts with another hydroxyl radical to form hydrogen peroxide. OH* + OH* H 2O 2
  19. 19. Free Radicals  A free radical is an atom or molecule that has an unpaired electron in its valence shell.  These free radicals are non-selective when pairing up with electrons from other atoms, including those that make up the DNA molecule.
  20. 20. Direct Action / Indirect Action Direct Action Causes damage directly to DNA or other important molecules in the cell. More likely when the beam of charged particles consist of alpha particles, protons, or electrons Indirect Action Causes damage by interacting with the cellular medium producing free radicals which then damage the DNA molecule. More likely when x-rays or gamma-rays compose the beam.
  21. 21. Direct Action / Indirect Action
  22. 22. DNA Damage  The arrangement of nitrogenous bases    provide a blueprint for DNA for the synthesis of specific proteins necessary for individual cell function. In the event of a loss or change of one or more of the nitrogenous bases....base sequence and normal functioning of the cell is altered. Another form of DNA damage due to radiation involves a break in the hydrogen bonds between the Adenine – Thymine and Cytosine – Guanine base pairs. These bonds function to keep the DNA strands together Bonds can also break between deoxyribose sugar and the phosphate groups which can lead to cross-linking of DNA The target
  23. 23. Chromosome Aberrations The effects  If the chromosome fragments are   near one another they have a high chance of reattaching in their original position – causing no future damage to the cell.A process known as restitution. In translocations and inversions, no genetic information is lost, but the rearrangement of gene sequence will alter protein synthesis. In a deletion, a chromosome fragment is not replicated during the next mitosis, the genetic information is lost. The effects this has on the cell depends on the amount and type of information lost. Inversion Translocation Deletion
  24. 24. Chromosome deletion Chromosome translocation
  25. 25. Outcomes after cell exposure DAMAGE TO DNA DAMAGE REPAIRED IAEA CELL DEATH (APOPTOSIS) TRANSFORMED CELL 3 : Biological effects of ionizing radiation
  26. 26. Viable Cell Mutation repaired Cell death Unviable Cell Cancer ? DNA Mutation Cell survives but mutated
  27. 27. Repair of DNA damage • RADIOBIOLOGISTS ASSUME THAT THE REPAIR SYSTEM IS NOT 100% EFFECTIVE. IAEA 3 : Biological effects of ionizing radiation
  28. 28. Cancer initiation
  29. 29. NORMAL TISSUE
  30. 30. CELL INITIATION An initiating event creates a mutation in one of the basal cells
  31. 31. DYSPLASIA More mutations occurred. The initiated cell has gained proliferative advantages. Rapidly dividing cells begin to accumulate within the epithelium.
  32. 32. BENIGN TUMOR More changes within the proliferative cell line lead to full tumor development.
  33. 33. MALIGNANT TUMOR The tumor breaks trough the basal lamina. The cells are irregularly shaped and the cell line is immortal. They have an increased mobility and invasiveness.
  34. 34. METASTASIS Cancer cells break through the wall of a lymphatic vessel or blood capillary. They can now migrate throughout the body and potentially seed new tumors.
  35. 35. A simple generalized scheme for multistage oncogenesis Damage to chromosomal DNA of a normal target cell Failure to correct DNA repair Appearance of specific neoplasia-initiating mutation Promotional growth of pre-neoplasm Conversion to overtly malignant phenotype Malignant progression and tumour spread
  36. 36. Radiosensitivity Actively reproducing cells are more radiosensitive than mature cells. During mitosis, the cell is in a stressed state and shows an increase in damage caused by radiation. Cells that have decreased levels of differentiation are more radiosensitive than specialized cells.
  37. 37. The Cell Cycle G2 (2nd gap) M (mitosis)  G1 (1st gap) S (DNA Synthesis phase)  Cells that cease division An ordered set of events, culminating in cell growth and division into two daughter cells Tc, full mitotic cycle
  38. 38. Radiosensitivity & Mitotic Cycle  Cell cycle components   Cell cycles times vary largely due to G1    M, G1, S, G2 crypt cells, 9 - 10 hours stem cells (mouse skin) 200 hr Sensitivity     Cells most sensitive close to mitosis Resistance greatest in latter part of S For long G1’s, there is an early resistance period followed by sensitive one at the end of G1 G2 ~ M in sensitivity
  39. 39. Radiosensitivity High RS Bone Marrow Spleen Thymus Lymphatic nodes Gonads Eye lens Lymphocytes Medium RS Skin Mesoderm organs (liver, heart, lungs…) Low RS Muscle Bones Nervous system (exception to the RS laws) IAEA 3 : Biological effects of ionizing radiation
  40. 40. Fractionation in radiotherapy  Instead of a single treatment consisting of a high dose, fractionation divides the dose to be delivered over a period of time, usually 6-8 weeks.  At low doses of radiation, normal cells have an increased survival rate because of their ability to repair sublethal damage before the next fraction of radiation is delivered.  Tumor cells do not possess the repair enzymes necessary to keep up with the repairs and as a result the cell is overwhelmed and is destroyed. http://www.usoncology.com/CompanyInfo/PhotoLibrary.asp
  41. 41. Dose-Response Relationships  Two effects of radiation exposure:    deterministic (threshold) stochastic: cancer Radiation Standards   set below threshold set to limit stochastic risk
  42. 42. Non-Stochastic (Deterministic) Effects   Occurs above threshold dose Severity increases with dose      Alopecia (hair loss) Cataracts Erythema (skin reddening) Radiation Sickness Temporary Sterility
  43. 43. Stochastic (Probabilistic) Effects   Occurs by chance Probability increases with dose    Carcinogenesis Mutagenesis Teratogenesis
  44. 44. Radiation health effects TYPE OF EFFECTS CELL DEATH CELL TRANSFORMATION DETERMINISTIC STOCHASTIC Somatic Clinically attributable in the exposed individual somatic & hereditary IAEA epidemiologically attributable in large populations BOTH ANTENATAL somatic and hereditary expressed in the foetus, in the live born or descendants 3 : Biological effects of ionizing radiation
  45. 45. Radiation effects and Syndromes
  46. 46. Skin reactions Threshold Injury Dose to Skin (Sv) Early transient erythema Temporary epilation Main erythema Permanent epilation Dry desquamation Invasive fibrosis Dermal atrophy Telangiectasis Moist desquamation Late erythema Dermal necrosis Secondary ulceration IAEA 2 3 6 7 10 10 11 12 15 15 18 20 Weeks to Onset <<1 3 1.5 3 4 >14 >52 4 6-10 >10 >6 3 : Biological effects of ionizing radiation Skin damage from prolonged fluoroscopic exposure
  47. 47. Skin injuries IAEA 3 : Biological effects of ionizing radiation
  48. 48. Effects in eye Histologic view of eye: • Eye lens is highly RS. • Coagulation of proteins occur with doses greater than 2 Gy. • There are 2 basic effects: Effect From “Atlas de Histologia...”. J. Boya Eye lens is highly RS, moreover, it is surrounded by highly RS cuboid cells. IAEA Detectable opacities Visual impairment (cataract) Sv single brief exposure Sv/year for many years 0.5-2.0 > 0.1 5.0 > 0.15 3 : Biological effects of ionizing radiation
  49. 49. Whole body response: adult Acute irradiation syndrome 1-10 Gy Steps: 10 - 50 Gy Survival time Chronic irradiation syndrome > 50 Gy BONE MARROW GASTRO INTESTINA L 1. Prodromic (onset of disease) 2. Latency 3. Manifestation CNS Lethal dose 50 / 30 • Mechanism: Neurovegetative disorder • Similar to a sick feeling • Quite frequent in fractionated radiotherapy (central nervous system) IAEA Dose 3 : Biological effects of ionizing radiation 49
  50. 50. Threshold Doses for Deterministic Effects • Cataracts of the lens of the eye 2-10 Gy • Permanent sterility • males 3.5-6 Gy • females Severity of effect 2.5-6 Gy • Temporary sterility • males • females 0.15 Gy 0.6 Gy dose threshold
  51. 51. Symptoms of Acute Radiation Sickness  Three categories (E. Hall, 1994)  Hemopoietic: 3-8 Gy LD50/60      radiation damages precursors to red/white blood cells & platelets prodromal may occur immediately symptoms: septicemia, survival mixed examples include Chernobyl personnel (203 exhibited symptoms, 13 died)
  52. 52. Symptoms, continued  Gastrointestinal : >10 Gy      radiation depopulates GI epithelium (crypt cells) abdominal pain/fever, diarrhea, dehydration death 3 to 10 days (no record of human survivors above 10 Gy) examples include Chernobyl firefighters Cerebrovascular : > 100 Gy  death in minutes to hours
  53. 53. Delayed Effects   SOMATIC: they affect the health of the irradiated person. They are mainly different kinds of cancer (leukemia is the most common, with a delay period of 2-5 years, but also colon, lung, stomach cancer…) GENETIC: they affect the health of the offspring of the irradiated person. They are mutations that cause malformation of any kind (such as mongolism)
  54. 54. Summary     Effects of ionizing radiation may be deterministic and stochastic, immediate or delayed, somatic or genetic Some tissues are highly radiosensitive Each tissue has its own risk factor Risk from exposure may be assessed through such factors
  55. 55. Where to Get More Information (1) • The 2007 Recommendations of the International Commission on Radiological Protection, ICRP 103, Annals of the ICRP 37(2-4):1-332 (2007) • UNSCEAR 2008 Report to the General Assembly, with scientific annexes, United Nations Scientific Committee on the Effects of Atomic Radiation, United Nations, Vienna, Austria, 2008 • Avoidance of radiation injuries from medical interventional procedures. ICRP Publication 85. Ann ICRP 2000;30 (2). Elsevier IAEA 3 : Biological effects of ionizing radiation 56

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